A fundamental issue in the study of learning and memory is the functional relationship between synaptic structure and the profound changes in synaptic effectiveness the accompany long-term behavioral modifications. The research outlined in this proposal is designed to focus on this problem by examining the morphological basis of the synaptic plasticity that underlies simple forms of learning and memory. Toward this end we propose t use a model system, themarine mollusc Aplysia californica, in which a variety of behavioral modifications (short-term and long-term, non-assoicative and associative) can be studied to advantage on the cellular and on the molecular level. An elementary defensive behavior in Aplysia, the gill- and siphon-withdrawal reflex, undergoes two simple forms of learning -- habituation and sensitization. Both involve changes in synpatic efficacy at a common synaptic locus -- the presynaptic terminals of identified sensory neurons. Recently, my colleagues and I have developed a variety of cell marking and ultrastructural techniques to describe the structure and organization o the critical synapses that mediate both habituation and sensitization in Aplysia. In addition we have developed a greatly simpligied peripheral nervous sysem preparation that provides the unique opportunity to examine the intramembranous architecture of synapses following behavioral modification. We now propose to take advantage of this normative data to explore morphological and molecular alterations that may accompany simple forms of learning and memory. Our studies of learning will address specific questions at two different levels of biological organization: at the ultrastructural level we plan to study the morphological correlates of long-term habituation and sensitization by examining the presynaptic terminals of sensory neurons following these behavioral modifications. At the molecular level we plan to combine a greatly simplified peripheral preparation and freeze-fracture to examine the effects of synaptic plasticity ont he intramembranous organization of the active zone. These studies should prove useful for examining the cellular mechanisms that underly long-term behavioral modifications and may also increase our understanding of how the functional architecture of the synapse is related to its plastic capabilities.